Remote moderate-severe traumatic brain injury (cTBI) has long been viewed as a risk factor for Alzheimer's disease (AD) and AD related dementias (ADRD). Yet, autopsy evidence now shows that TBI pathologies include an aggregation of various neurodegenerative disease proteins and other pathologies (e.g. white matter degeneration). These relationships and the pathologies initiated might depend on the severity and number of TBIs. Growing research links repetitive head impacts (RHI) from contact sports and military service with AD, ADRD and the neurodegenerative disease, chronic traumatic encephalopathy (CTE). RHI has been associated with other pathologies, such as white matter degeneration and neuroinflammation. Although unknown, it is thought that RHI leads to AD, ADRD, CTE, and other pathologies via recurrent concussions and asymptomatic subconcussions. Evidence also suggests that a single cTBI is sufficient to precipitate AD, ADRD and CTE. The pathological substrates of the various TBI exposures remain unclear and the severity and number of TBIs needed to confer risk for AD, ADRD, CTE, and other pathologies is unknown. Research on the chronic pathologies of RHI is limited by lack of consideration for the role of TBI, focus on male football players, lack of ?controls,? recruitment bias, and failure to account for genetic and non-genetic risk factors. This project will address these limitations and examine the association of RHI and TBI (of all severities) with AD, ADRD, CTE, and other pathologies, as well as investigate genetic and non-genetic modifiers of these effects. We will examine how RHI and TBI interact to lead to AD, ADRD, CTE, and other pathologies. The overarching hypotheses are that RHI and TBI will have distinct pathological associations that will be modified by genetic and non-genetic risk factors. We will leverage the infrastructure of our ongoing NIH-funded UNITE study. We will harmonize 6 brain banks at Boston University, and the AD Research Center and Late Effects of TBI brain banks at Mount Sinai. Outcomes will include AD, ADRD, and CTE status, and semi- and quantitative measures of neurodegenerative proteins and other pathologies. We will add harmonized methods across brain banks for the assessment of RHI and TBI and examine 1500 brain donors: 1000 exposed to RHI/TBI, including various contact sport athletes, military veterans, and donors with remote TBI (mild-severe); and 500 demographically-similar non-RHI/TBI brain donors. We will collect RHI and TBI data on new brain donors, assess RHI and TBI for 400 brain donors from two brain banks (BU and Mount Sinai AD Centers) where RHI and TBI have been unassessed, and leverage existing RHI and TBI data from brain banks. Selection bias will be addressed by including brain banks that do not recruit based on RHI/TBI, inverse probability weighting, and simulation models. This project will result in the largest brain donor cohort with harmonized, well-characterized RHI and TBI histories. It will include contact sport athletes across different sports and levels of play, military veterans, and brain donors with remote TBIs (mild-severe). Findings will inform on the specific risks for AD, ADRD, CTE, and other chronic pathologies from RHI and TBI.